Balloon + Oxytocin versus Oral Misoprostol to Induce labor in case of premature rupture of membranes (PROM) at term in nulliparous

The primary objective of this study is to demonstrate a higher rate of vaginal birth within 24 hours by using a combination of a balloon catheter and **oxytocin** after 6 hours, compared to a low dose of oral **misoprostol** (25 µg oral PGE1 every 2 hours) in cases of unfavorable cervix beyond 12 hours of premature rupture of membranes (PROM) in nulliparous women. This is clinically relevant as it aims to optimize labor induction methods, potentially reducing the duration of labor and improving maternal and neonatal outcomes.

Secondary objectives include:

• Comparing the rate of caesarean sections between the two groups.
• Evaluating the safety related to women of both induction methods in terms of maternal morbidities, uterine hyperstimulation, maternal infections, and other reported adverse events (AEs).
• Assessing the safety related to neonates of both induction methods in terms of neonatal morbidities, neonatal infections, and other reported AEs.

The clinical trial involves **pregnant women with premature rupture of membranes** (PROM) who are nulliparous and have an unfavorable cervix. The study population is exclusively female, with participants being over 18 years of age and having a gestational age of at least 37 weeks. The trial focuses on a vulnerable population, specifically targeting women with a singleton pregnancy and cephalic presentation. Participants must have experienced PROM at or beyond 37 weeks and 0 days, without labor occurring beyond 12 hours. The trial does not include male subjects. The sponsor has not provided information regarding the total number of participants. Participants are required to be able to give informed consent, comply with study requirements, and be covered by the French Social Security welfare system. The selection criteria ensure that the study population is homogenous in terms of gestational and health status, allowing for a focused investigation of the trial's objectives.

The clinical trial is designed to evaluate the efficacy of **oxytocin** combined with a balloon catheter versus oral **misoprostol** for inducing labor in pregnant women with premature rupture of membranes (PROM) at term. This study is a randomized, double-blind, controlled trial with an estimated duration from September 2022 to October 2024. Participants will be randomly assigned to receive either the balloon catheter with **oxytocin** or oral **misoprostol**. The primary objective is to assess the rate of vaginal birth within 24 hours and compare patient satisfaction using the EXIT survey.

The trial will include several study visits. The initial visit will be a screening visit to confirm eligibility based on criteria such as age over 18, gestational age of at least 37 weeks, singleton pregnancy with cephalic presentation, and an unfavorable cervix. Participants must provide informed consent and be able to comply with study requirements. Follow-up visits will monitor the induction process, including the duration from rupture to induction, the duration of balloon or **misoprostol** exposure, and the Bishop score on balloon removal. The end-of-study visit will evaluate outcomes such as the rate of vaginal delivery, cesarean section, and any adverse events.

Participant involvement is expected to last up to 2 days post-delivery, with the primary endpoint assessed within 24 hours of induction. Conditions that may lead to early termination from the study include withdrawal of consent, inability to comply with study procedures, or any medical condition that contraindicates continued participation. The trial aims to provide valuable insights into the optimal method for labor induction in cases of PROM, with a focus on both clinical outcomes and patient satisfaction.

The clinical trial involves the administration of several treatments, including **oxytocin**, **misoprostol**, **clindamycin**, **amoxicillin**, and **amoxicillin sodium**. **Oxytocin** is provided as a **solution for infusion** and is administered **intravenously**. The maximum daily dose is 10 IU, with a total dose not exceeding 10 IU over a treatment period of 1 day. The administration of oxytocin is facilitated by a transcervical balloon catheter, specifically a three-way ureteral silicon coude tip Foley catheter with a 60 cc balloon capacity, manufactured by Teleflex Medical.

**Misoprostol** is administered in **tablet** form and taken **orally**. The maximum daily dose is 200 µg, with a total dose of 200 µg over a 1-day treatment period. Misoprostol acts as a synthetic analogue of prostaglandin E1 and is used in this trial to induce labor in cases of premature rupture of membranes (PROM) at term in nulliparous women.

**Clindamycin** is provided as a **solution for injection** and administered **intravenously**. The maximum daily dose is 1800 mg, with a total dose not exceeding 3600 mg over a 2-day treatment period. Clindamycin serves as an auxiliary antibiotic treatment in the trial.

**Amoxicillin** is administered in **tablet** form and taken **orally**. The maximum daily dose is 3 g, with a total dose of 6 g over a 2-day treatment period. Amoxicillin is used as an auxiliary antibiotic treatment in the study.

**Amoxicillin sodium** is provided as a **powder for solution for infusion** and administered **intravenously**. The maximum daily dose is 2 g, with a total dose of 2 g over a 1-day treatment period. Amoxicillin sodium is also used as an auxiliary antibiotic treatment in the trial.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include the proportion of patients who achieve vaginal delivery within 24 hours, evaluated as a binary outcome (Yes/No), and the satisfaction of women with the induction method. This satisfaction will be measured between the second day after delivery and hospital discharge using the EXperience of Induction Tool (EXIT), which is validated in French. The EXIT tool will explore three dimensions: the time taken to give birth, discomfort with induction of labor (IOL), and the experience of subsequent contractions.

Secondary endpoints will provide additional insights into the efficacy of the interventions. These include the duration from rupture to the beginning of induction, the duration between IOL and delivery, and the duration of balloon or misoprostol exposure. Other secondary measures include the total dose of misoprostol received, Bishop score upon balloon removal, and the rate of balloon in place at 12 hours. Additional outcomes such as the duration until full cervical dilatation, rates of spontaneous vaginal or instrumental delivery, cesarean section rates, and post-partum hemorrhage rates will also be evaluated. Maternal and neonatal outcomes, including fever during labor, uterine hyperstimulation, endometritis, hospital stay duration, birth weight, Apgar score, umbilical artery pH, and rates of transfer to intensive care or neonatology units, will be assessed. The rate of maternal-fetal infection and age at hospital discharge are also included as secondary endpoints.